TPP-45142-an Anti-HER2 T-cell Engager-Designed for Selective HER2-Low Cancer Immunotherapy.

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• Standard treatments for HER2-positive cancers exist, but HER2-low and trastuzumab-refractory cancers remain a challenge.
• Trastuzumab and pertuzumab target specific HER2 epitopes, leaving a gap in treatment for certain patient populations.

Purpose of the Study:

• To develop and evaluate TPP-45142, a novel NANOBODY® domain-based T cell engager (TCE), for targeting HER2-low cancers.
• To assess the efficacy and safety of TPP-45142 in preclinical models of HER2-low breast, gastric, and gastroesophageal junction adenocarcinoma.

Main Methods:

• Development of TPP-45142, a TCE utilizing a NANOBODY® domain and T cell receptor (TCR)αβ.
• In vitro assessment of T cell-dependent cytotoxicity against HER2-low cancer cell lines.
• In vivo evaluation of TPP-45142 efficacy in HER2-low breast cancer xenograft models.
• Assessment of TPP-45142 selectivity for tumor cells versus normal cardiac cells and cytokine release assay.

Main Results:

• TPP-45142 demonstrated potent T cell-dependent killing of HER2-low cancer cells in vitro.
• In vivo studies showed TPP-45142 inhibited tumor growth in HER2-low breast cancer xenografts.
• TPP-45142 exhibited high selectivity for HER2-low tumor cells over normal cardiac cells, with a favorable therapeutic index.

Conclusions:

• TPP-45142 is a promising next-generation TCE targeting HER2-low cancers.
• The molecule recognizes a distinct HER2 epitope, offering a new therapeutic avenue.
• TPP-45142 presents an improved safety profile, addressing unmet needs in HER2-targeted therapy.